Product Substitution

Alkanes also react with halogens to form substitution products. 

One of the characteristic properties of phenol is the ease with which it gives substitution products, this property being particularly well shown by the ready nitration, sulphonation and bromination which the benzene ring in the phenol molecule undergoes. 

The sodio derivative, which is prepared by mixing alcoholic solutions of the ester and of sodium ethoxide, condenses with alkyl halides to yield mono-alkyl C-substituted products, for example ... 

The mono-alkyl C-substituted derivatives of ethyl acetoacetate upon treatment with sodium ethoxide and another molecule of alkyl halide afford the di-alkyl C-substituted products... 

Mono-substitution products of primary amines cannot easUy be prepared by direct action of the appropriate reagent for example, bromination of aniline yields largely the 2 4 6-tribomo derivative and nitration results in much oxidation. If, however, the amino group is protected as in acetanilide, smooth substitution occurs. Thus with bromine, />-bromoacetanilide is the main product the small quantity of the ortlio isomeride simultaneously formed can be easily eliminated by crystallisation. Hydrolysis of p-bromoacetanilide gives/ -bromoaniline ... 

Because of the chemical similarity between benzoyl nitrate and the acetyl nitrate which is formed in solutions of nitric acid in acetic anhydride, it is tempting to draw analogies between the mechanisms of nitration in such solutions and in solutions of benzoyl nitrate in carbon tetrachloride. Similarities do exist, such as the production by these reagents of higher proportions of o-substituted products from some substrates than are produced by nitronium ions, as already mentioned and further discussed below. Further, in solutions in carbon tetrachloride of acetyl nitrate or benzoyl nitrate, the addition of acetic anhydride and benzoic anhydride respectively reduces the rate of reaction, implying that dinitrogen pentoxide may also be involved in nitration in acetic anhydride. However, for solutions in which acetic anhydride is also the solvent, the analogy should be drawn with caution, for in many ways the conditions are not comparable. Thus, carbon tetrachloride is a non-polar solvent, in which, as has been shown above,... 

If, on the other hand, the encounter pair were an oriented structure, positional selectivity could be retained for a different reason and in a different quantitative sense. Thus, a monosubstituted benzene derivative in which the substituent was sufficiently powerfully activating would react with the electrophile to give three different encounter pairs two of these would more readily proceed to the substitution products than to the starting materials, whilst the third might more readily break up than go to products. In the limit the first two would be giving substitution at the encounter rate and, in the absence of steric effects, products in the statistical ratio whilst the third would not. If we consider particular cases, there is nothing in the rather inadequate data available to discourage the view that, for example, in the cases of toluene or phenol, which in sulphuric acid are nitrated at or near the encounter rate, the... 

The rate of the reaction decreases with increasing number of substituents in the acetylenic halide, and it is higher with acetylenic bromides than with the corresponding chlorides. Methyl magnesium iodide gives equal amounts of 1,1- and 1,3--substitution products, whereas tert.-butylmagnesium bromide does not react. However, for some tert.-butyl substituted allenes there exists an attractive com-... 

Note 2. A large number of experimental examples are given in Ref. 108. In some cases methyl sulfonates can be successfully applied when the use of the sulfinic esters leads to mixtures of 1,1- and 1,3-substitution products. 

After cooling to about 40°C (note 2) the viscous brown liquid was poured into a vigorously stirred solution of 50 g of ammonium chloride in 250 ml of 4 N HCl, which was kept at 0-5°C. The flask was also rinsed with this solution. The product was extracted 5-7 times with a 1 1 mixture of diethyl ether and pentane. The combined extracts were washed with saturated NHi Cl solution and subsequently dried over magnesium sulfate. The residue remaining after removal of the solvents in a water-pump vacuum, was carefully distilled through a 30-cm Widmer column. The desired nitrile, b.p. 84°C/15 mmHg, n 1.4487, was obtained in 72% yield. The first fraction (about 5 g) consisted mainly of the 1,3-substitution product n-C,HgC(CsN)=C=CH2. 

J-Tosyloxy. d -steroids, e.g. O-tosylcholesterol, give 3,5-cyclosteroids (— /-steroids) on addition of nucleophiles. Internal hydroxyl displacement, e.g. with PClj, leads to 3fi-substituted products or overall retention of configuration at C-3 by rearrangement of the 6/5 substituent (E.M. Kosower, 1956). 

The Pd—C cr-bond can be prepared from simple, unoxidized alkenes and aromatic compounds by the reaction of Pd(II) compounds. The following are typical examples. The first step of the reaction of a simple alkene with Pd(ll) and a nucleophile X or Y to form 19 is called palladation. Depending on the nucleophile, it is called oxypalladation, aminopalladation, carbopalladation, etc. The subsequent elimination of b-hydrogen produces the nucleophilic substitution product 20. The displacement of Pd with another nucleophile (X) affords the nucleophilic addition product 21 (see Chapter 3, Section 2). As an example, the oxypalladation of 4-pentenol with PdXi to afford furan 22 or 23 is shown. 

Under certain conditions, the /(-substitution products are obtained as major products[66]. Methyl vinyl ether reacts with bromonitrobenzene to give the f-methoxystyiene 64 in good yield in toluene at 120 "C by using Pd on carbon as... 

Zugravescu reports the isolation of ring nitrogen substitution products (195) (Scheme 124) (325). and it is not clear whether direct electrophilic substitution in the 5-position is the general case or if the finally observed product results from rearrangement. 

Acrylonitrile reacts with the sodium salt of 4.5-dimethvl-A-4-thiazoline-2-thione (73J (R4 = R5 = Me) to yield 3-(2-cyanoethyl)-4.5-dimethyl-A-4-thiazoline-2-thione (74) (R4 = R, = Me) (Scheme 35 (160). Humphlett s studies of this reaction showed that the size of the R4 substituent is a determinant factor for the S versus N ratio (161. 162). If R4 == H, 100% of the N-substituted product (74) is obtained this drops to 50% when R4 = methyl, and only the S-substituted product (75) is obtained when R4 = phenyl. The same trend is observed with various CH2 = CH-X (X = C00CH3. COCH3) reagents (149). The S/N ratio also depends on the electrophilic center for CH2 = CH-X systems thus S-reaction occurs predominantly with acrylonitrile, whereas N-substitution predominates with methvlvinvlketone (149). 

Alkylation by diazoalkanes gives more N-substituted product when the reaction goes through an S l transition state. Representative data are given in Table Vll-lOa. and they are discussed in Ref. 101. 

Grignard reagent comes from the substitution products it gives with various reactive substrates. When the low-temperature adduct is heated in an autoclave at 90 to 170 C for 3 to 6 hr, it does not rearrange to 2-ethylthiazole (12) as is the case in the pyridine series (436). 

The 2-metalated thiazoles react with a variety of electrophilic substrates in a standard way, leading to addition products with aldehydes, ketones, carbon dioxide, epoxides, nitriles, Schiff bases, and to substitution products with alkyl iodides (12, 13, 437, 440). 

The more reactive bromacetone gives not only 2-mercapto-4-methylthiazole but also its substitution products. The higher homologs, as far as C15. are obtained in reasonably good yield in absolute ethanol (150, 156. 234. 316, 530). The best result (85%) was obtained by working in aqueous solution with the 3-bromobutan-2-one (597). 

The reaction of 2.4-dimethylthiazole with butyllithium shows that, in contrast to 2-methylthiazole, the benzyl position (the 2-position) is the most reactive. The effect of the substituent in the 4-position may well be steric 4-r-butyl-2-methylthiazole in the same reaction gives no 5-substituted product (223). 

Benzylthiazole reacts with n-butyllithium to give 2- and 5-substituted products, but as expected from the particular properties of the 2-methyiene group, the proportion of 2-lithium derivatives is much more important (223). 

Regarding the substituent effect on reactivity of groups in positions 4 and 5 there is little information in the literature. The reactivity of halogen in position 5 seems to be increased when an amino group is present in position 2. Substitution products are easily obtained using neutral nucleophiles such as thiourea, thiophenols, and mercaptans (52-59). 

Additional evidence for carbocation intermediates in certain nucleophilic substitutions comes from observing rearrangements of the kind normally associated with such species For example hydrolysis of the secondary alkyl bromide 2 bromo 3 methylbutane yields the rearranged tertiary alcohol 2 methyl 2 butanol as the only substitution product... 

Hydrogen sulfide ion HS and anions of the type RS are substantially less basic than hydroxide ion and react with both primary and secondary alkyl halides to give mainly substitution products... 

Regardless of the alkyl halide raising the temperature increases both the rate of substitution and the rate of elimination The rate of elimination however usually increases faster than substitution so that at higher temperatures the proportion of ehm mation products increases at the expense of substitution products... 

Solvolysis of 1 2 dimethylpropyl p toluenesulfonate in acetic acid (75°C) yields five differ ent products three are alkenes and two are substitution products Suggest reasonable structures for these five products... 

If the Lewis base ( Y ) had acted as a nucleophile and bonded to carbon the prod uct would have been a nonaromatic cyclohexadiene derivative Addition and substitution products arise by alternative reaction paths of a cyclohexadienyl cation Substitution occurs preferentially because there is a substantial driving force favoring rearomatization Figure 12 1 is a potential energy diagram describing the general mechanism of electrophilic aromatic substitution For electrophilic aromatic substitution reactions to... 

Two isomeric arynes give the three isomeric substitution products formed from m chloro toluene... 

Focants of substituents of symmetrically substituted derivatives of symmetrical amines are distinguished by primes or else the names of the complete substituted radicals are enclosed in parentheses. Unsymmetrically substituted derivatives are named similarly or as A-substituted products of a primary amine (after choosing the most senior of the radicals to be the parent amine). For example. 

Many of the common electrophilic aromatic substitution reactions can be conducted on indole. CompHcations normally arise either because of excessive reactivity or the relative instabiUty of the substitution product. This is the case with halogenation. 

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